The present invention relates to antiinfectives, antibiotics, oral antibiotics, and prodrugs, in particular, sulopenem prodrugs, their preparation, and use.
U.S. Pat. No. 5,013,729 describes sulopenem, which is a broad-spectrum antibiotic that can be named as (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(1R,3S)-tetrahydro-1-oxido-3-thienyl]thio]-4-thia-1-azabicyclo[3,2.0]hept-2-ene-2-carboxylic acid. See also J. Org. Chem., 57, 4352-61 (1992).
Other penems and prodrugs are discussed in, e.g., U.S. Pat. No. 4,952,577; U.S. Pat. No. 5,506,225, WO1992/003444; and WO2004/067532.
Various preclinical and clinical studies have been conducted with sulopenem and certain prodrugs thereof. Sulopenem itself is not appreciably orally bioavailable. U.S. Pat. No. 5,013,729 also discusses sulopenem prodrugs, including the pivaloyloxymethyl prodrug of sulopenem (sulopenem POM ester). When given orally as a mixture of two stereoisomers, the POM ester was shown to be orally bioavailable in humans. See Foulds et al., Antimicrobial Agents and Chemotherapy, pp. 665-671 (April 1991). However, POM ester prodrugs are associated with tissue carnitine depletion following hydrolysis and release of pivalic acid or trimethyl acetic acid. See Brass, Pharmacological Reviews, 54, 589-598 (2002).